本文選題：ADEPT + 前藥��； 參考：《北京協(xié)和醫(yī)學(xué)院》2014年碩士論文

【摘要】：抗體導(dǎo)向的酶前體藥物療法(ADEPT)利用抗體-抗原、酶-前藥特異性來介導(dǎo)細(xì)胞毒性藥物對(duì)腫瘤部位的選擇性殺傷作用。其中,酶具有低免疫原性及高效性,前藥低毒并可被相應(yīng)的酶高效轉(zhuǎn)化,對(duì)腫瘤細(xì)胞的殺傷作用呈濃度依賴型。因此,本實(shí)驗(yàn)根據(jù)低免疫原性的突變性β-內(nèi)酰胺酶的底物專一性,將β-內(nèi)酰胺酶的良好底物頭孢菌素類與氮芥類細(xì)胞毒藥物美法侖拼合,設(shè)計(jì)合成目標(biāo)化合物頭孢美法侖,并對(duì)其體外抗腫瘤活性進(jìn)行初步評(píng)價(jià)。 我們選擇GCLE作為原料,將其經(jīng)碘代反應(yīng)制成活性較高的GIE,而后與已酯化的美法侖進(jìn)行偶聯(lián),再將偶聯(lián)物進(jìn)行氧化和水解從而合成頭孢美法侖,終產(chǎn)物采用1H NMR及質(zhì)譜確證其結(jié)構(gòu)。體外抗腫瘤活性實(shí)驗(yàn)采用MTT毒性法,在設(shè)定濃度范圍內(nèi)測(cè)定前藥和原藥的抑制率(%)和IC50(μmol/l),結(jié)果表明：?jiǎn)吻八幣c空白對(duì)照組的結(jié)果不存在顯著性差異,在體外基本無毒；酶解前藥和陽性對(duì)照藥均對(duì)該腫瘤細(xì)胞具有顯著性殺傷作用,IC50分別為101.97±1.70μ mol/l和66.69±0.37μmol/l;酶解前藥對(duì)腫瘤細(xì)胞的殺傷作用呈濃度依賴性。由此可見,本實(shí)驗(yàn)設(shè)計(jì)合成的頭孢美法侖前藥與原藥美法侖相比,細(xì)胞毒作用相差不多,但由于ADEPT系統(tǒng)的靶向性,具有體外無毒及靶向殺傷等優(yōu)點(diǎn),是一頗具前景的腫瘤治療候選藥物。
[Abstract]:Antibody-directed enzyme precursor drug therapy (ADEPTT) mediates the selective killing effect of cytotoxic drugs on tumor sites by using antibody-antigen and enzyme-prodrug specificity. Among them, the enzyme has low immunogenicity and high efficiency. Prodrug has low toxicity and can be transformed by the corresponding enzyme. The killing effect of prodrug on tumor cells is concentration-dependent. Therefore, according to the substrate specificity of low immunogenicity mutant 尾 -lactamases, cephalosporins, a good substrate of 尾 -lactamases, were combined with melfarin, a cytotoxic drug of nitrogen mustard, to design and synthesize the target compound cefmefacalam. The anti-tumor activity in vitro was evaluated. We selected GCLE as the raw material, and then synthesized cefmefacalen by oxidation and hydrolysis of the coupling material, which was prepared by iodine substitution reaction, and then was coupled with the esterified mefacalen. The final product was characterized by 1H NMR and mass spectrometry. In vitro antitumor activity test was carried out by MTT toxicity method. The inhibitory rates of prodrug and prodrug were determined within a given concentration range) and IC50 (渭 mol / L). The results showed that there was no significant difference between the single prodrug and the blank control group, and the results were basically non-toxic in vitro. The IC50 of pre-enzymatic drugs and positive control drugs were 101.97 鹵1.70 渭 mol/l and 66.69 鹵0.37 渭 mol / L, respectively. It can be seen that the cytotoxicity of cefmefacalen prodrug designed and synthesized in this experiment is not much different from that of the original drug, but because of the targeting of ADEPT system, it has the advantages of non-toxic and targeted killing in vitro, and so on. It is a promising candidate for cancer therapy.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914.5;R96

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本文編號(hào)：1868112